The history of malaria as a serious human disease dates back to ancient times. For centuries, malaria has been a deadly disease with high morbidity and mortality that profoundly impacted the socioeconomic status of endemic countries. However, its causative agent remained unidentified until the last decades of the nineteenth century. There were no effective synthetic anti-malarial agents until the mid-twentieth century. Currently malaria has been eliminated or pre-eliminated in numerous countries; however, this preventable and curable disease remains a significant global health problem. A major concern is drug resistance. Presented here, is a brief look at the history of malaria in Iran and the rest of the world, particularly during the nineteenth and twentieth centuries.